Table 1 provides a summary of the clinical trials evaluating the 3′-AmNic-rEPA vaccine in human subjects.[14,18–21] An initial phase I–II, randomized, double-blind, placebo-controlled trial evaluated the safety and immunogenicity of the 3′-AmNic-rEPA vaccine in human subjects. A total of 30 male and female participants (21 smokers, 9 nonsmokers) in good health and aged 24–60 years were included in the study. Participants were considered to be smokers if they smoked at least 15 cigarettes/day. Subjects taking any of the following drugs were excluded from the study: antihistamines, psychotropic drugs, systemic corticosteroids, immunosuppressive agents, nicotine replacement therapy, illicit drugs, or any other agent that may affect vaccine immunogenicity. As this study was not intended to assess vaccine efficacy, and researchers wanted to determine the effects of smoking on the immunogenicity of the vaccine, smokers were included in the study only if they were not interested in quitting within the 6 months after the initial screening visit.
The primary objectives of this study were to assess the safety and immunogenic properties of multiple 100-μg doses of the 3′-AmNic-rEPA vaccine. A secondary objective was to evaluate the effect of nicotine on vaccine immunogenicity in current smokers. Smokers and nonsmokers were randomly assigned in a 1:6 and 1:2 ratio, respectively, to receive four total injections of either placebo or the 3′-AmNic-rEPA vaccine. Ultimately, 24 participants received at least one dose of the active injection and six participants received placebo. Injections were administered into the deltoid muscle on alternating arms at baseline, 2 weeks, 1 month, and 6 months. Nicotine-specific antibody concentrations were measured on days 0, 7, 14, 21, 28, 35, 49, 84, 119, 182, 189, 217, and 266. Subjects were followed for 38 weeks.
Results from the study showed that after three doses of the 3′-AmNic-rEPA vaccine, the geometric mean titer of nicotine-specific antibodies in smokers was 8.8 μg/ml (95% confidence interval [CI] 4.7–16.4 μg/ml) and 9.7 μg/ml (95% CI 3.2–30.4 μg/ml) in nonsmokers. Nicotine-specific antibody levels measured in the active vaccine group before the final injection showed a decrease to a geometric mean titer of 3.4 μg/ml in smokers and 2.3 μg/ml in nonsmokers. Measurement of nicotine-specific antibody levels 1 week after the fourth booster dose demonstrated an increase of nicotine-specific antibody levels to 13.3 μg/ml (95% CI 7.1–25.1 μg/ml) in smokers and 4.4 μg/ml (95% CI 1.3–14.4 μg/ml) in nonsmokers. Differences in nicotine-specific antibody concentrations between smokers and nonsmokers were not statistically significant. In those participants receiving placebo injections, nicotine-specific antibodies were undetectable at all measurement points.
Local reactions to the 3′-AmNic-rEPA vaccine such as tenderness, ache, and swelling or induration were reported in 67%, 50%, and 38% of participants, respectively. Participants in the placebo group described tenderness (67%) and ache (50%) at rates similar to those receiving the active vaccine, whereas no participants in the placebo group reported swelling or induration at the injection site. Systemic reactions such as muscle ache, headache, and general discomfort were reported by 38%, 25%, and 25% of subjects receiving active vaccine, respectively, and 33%, 33%, and 50% of subjects in the placebo group, respectively. For both local and systemic reactions experienced by those in the active vaccine group, most were determined to be mild in nature. In addition to local and systemic reactions to the vaccine, adverse effects were reported. Individuals receiving the active vaccine reported bad taste (79%) and weight gain (41.6%). Weight gain was not reported by any participants in the placebo group; however, 83% of subjects in the placebo group complained of bad taste. The small sample size limited the ability to detect rare adverse effects that may be discovered in a larger population.
The authors concluded that the 3′-AmNicrEPA vaccine was capable of stimulating production of nicotine-specific antibodies in participants, with minimal adverse effects, and the immunogenicity of the vaccine was not affected by the concurrent administration of cigarette smoke.
A second phase II, randomized, double-blind, placebo-controlled trial was undertaken to further explore the safety and immunogenicity of the 3′-AmNic-rEPA vaccine and also to determine if the nicotine vaccine produces compensatory smoking behaviors as well as withdrawal symptoms. A total of 68 patients (77.9% male) were enrolled from three university sites. Male and female subjects aged 18 years or older were permitted to participate in the study if they met the following criteria: smoking at least 15 cigarettes/day, had been smoking for at least the past 6 months, no intention to quit smoking in the next 30 days, general good health, and good mental health. Exclusion criteria were any previous exposure to the nicotine vaccine or other vaccines within the previous 30 days, allergy to the vaccine components, drug or alcohol abuse, psychiatric history within the past 3 months, and use of systemic or inhaled corticosteroids, antihistamines, immunosuppressive drugs, or smoking cessation products within the previous 30 days from the date of the screening visit.
The primary objectives of the study were to further investigate the immunogenic properties of the 3′-AmNic-rEPA vaccine in increasing doses along with safety parameters associated with the vaccine. Secondary objectives included assessment of withdrawal symptoms, compensatory smoking behavior, and changes in tobacco use. Withdrawal symptoms were evaluated by using the Minnesota Nicotine Withdrawal Scale, an eight-item tool that assesses depression; insomnia; irritability, frustration, and/or anger; anxiety; difficulty concentrating; restlessness; increased appetite and/or weight gain; and cravings. The first seven items were assessed on a scale of 0–4 (0 = not present, 4 = severe) at weekly intervals unless a patient was making a quit attempt, then these symptoms were assessed daily for 2 weeks and then weekly. Cravings were evaluated separately on a scale of 0–4 with options also ranging from not present to severe.
Three doses of the 3′-AmNic-rEPA vaccine— 50, 100, and 200 μg—were each compared separately with placebo. Participants were randomly assigned to receive one of the three vaccine doses or placebo in an approximate 2:1 ratio. Vaccine administration occurred at different intervals from that of the previous study, with intramuscular injections given at baseline, 28 days (vs 2 wks), 56 days (vs 1 mo), and 182 days. Antibody concentrations were measured on day 0, 7, 14, 28, 35, 42, 56, 63, 70, 98, 182, 189, 231, and 266. Participants were followed for 38 weeks.
Sixteen, 15, and 14 participants received the 200-μg, 100-μg, and 50-μg doses, respectively, whereas 23 participants received placebo. In terms of immunogenicity, peak nicotine-specific antibody levels were achieved after the third injection for all groups receiving the active vaccine, with those in the 200-μg group reaching a geometric mean titer nicotine-specific antibody level greater than 30 μg/ml 2 weeks after the third injection. To assess compensatory smoking behaviors in participants, both mean and maximum daily cigarette intake information were collected and analyzed at 28-day intervals after the second, third, and fourth injections in both placebo and active vaccine groups. A statistically significant difference emerged between mean (p=0.04) and mean maximum (p=0.04) reduction in number of cigarettes smoked/day as antibody levels increased.
Although not an end point of the study, 6 (37.5%) of 16 smokers receiving the 200-μg dose of the vaccine quit smoking for at least 30 consecutive days compared with 2 (8.7%) of 23 smokers in the placebo group. Individuals in the 200-μg group demonstrated the shortest interval in time to achieve 30-day abstinence compared with all other groups (p=0.01). As no other interventions to assist with cessation were provided during the study, this was considered to be a vaccine-only effect. Safety data showed that, for those who quit smoking, a significant decrease in mean craving score was observed during the first 2 weeks of quitting compared with baseline scores (p=0.04). No statistically significant decrease in withdrawal symptoms from baseline was observed in those who were able to quit smoking (p=0.10). For nonquitters, no significant difference was found from baseline mean withdrawal scores or cravings compared with measurements after the second, third, and fourth injections in either the active vaccine or placebo group (p=0.30 for withdrawal scores, p=0.89 for cravings).
Tenderness and ache at the injection site were the most frequently reported local effects in vaccine recipients, whereas malaise, headache, and myalgias were the most common systemic reactions. No significant differences between vaccine and placebo groups were found in terms of frequency of local and systemic effects. Adverse events such as upper respiratory tract infection, cough, headache, and nasopharyngitis were considered to be related to the study drug in 7% of the nicotine vaccine recipients compared with 5% of participants in the placebo group.
Ultimately, this trial provided valuable insight into the potential to maximize the dose of the 3′-AmNic-rEPA vaccine without compromising safety. Evidence to indicate that the vaccine causes compensatory smoking behaviors or precipitates more severe withdrawal symptoms was not supported by the results of this trial.
The most recent data on the 3′-AmNic-rEPA vaccine come from a phase IIb, randomized, double-blind, placebo-controlled trial conducted in collaboration with the U.S. National Institute on Drug Abuse. This trial was designed to evaluate the efficacy, optimal dose, and optimal regimen of the 3′-AmNic-rEPA vaccine in preparation for phase III trials. Individuals included in the study had to smoke at least 15 cigarettes/day and be interested in quitting smoking. A primary end point of carbon monoxide–confirmed continuous abstinence for 8 weeks from the beginning of week 19 to the end of week 26 after baseline injection and secondary end points of 12-month abstinence, daily cigarette consumption, nicotine-specific antibody levels, safety, and nicotine dependence were assessed.
Participants were randomized into one of two groups: four injections of 3′-AmNic-rEPA 200 μg, 3′-AmNic-rEPA 400 μg, or placebo (group 1); or five injections of 3′-AmNic-rEPA 200 μg, 3′- AmNic-rEPA 400 μg, or placebo (group 2). Within each group, participants were randomized in a 1:1:1 ratio (200 μg:400 μg:placebo), resulting in 100 active and 50 placebo recipients in each group. In the four-injection group, injections were administered at week 0, 6, 12, and 26, whereas in the five-injection group, injections were given at week 0, 4, 8, 16, and 26. Serum nicotine-specific antibody concentrations were measured periodically at 16–17 different time points. A priori, individuals were defined as high nicotine-specific antibody responders if they were among the top 30% of antibody producers based on area under the concentration-time curve values.
A total of 301 participants aged 18 years or older, smoking an average of 24 cigarettes/day, were enrolled in the trial. At 6 months, 61 (30%) of 201 subjects receiving the vaccine were classified as reaching high nicotine-specific antibody levels. Participants classified as high nicotine-specific antibody responders in the active vaccine groups achieved significantly higher continuous 8-week abstinence rates than those receiving placebo injections (24.6% vs 12%, p=0.024). In those subjects receiving vaccine who did not achieve high nicotinespecific antibody levels (bottom 70% of responders), continuous 8-week quit rates were not statistically significantly different from those of the placebo group (9.3% vs 12%, p=0.46). After 12 months, of the 61 high responders who were receiving vaccine, 11 (18%) were able to achieve continuous abstinence, a statistically significant difference from the six participants in the placebo group able to achieve continuous abstinence (6%, p<0.014). High nicotine-specific antibody responders who were not able to quit smoking reduced the number of cigarettes smoked per day by an average of 50%.
Local reactions such as tenderness at the injection site and ache were reported commonly in both the active and placebo groups. Malaise, headache, and myalgia were the most common systemic reactions reported, occurring at equivalent rates in both the active and placebo groups. One subject from the 400-μg, five-injection active vaccine group, who had a history of urticaria from penicillin, developed an anaphylactic reaction 70 minutes after receiving the first vaccination. Subcutaneous epinephrine and diphenhydramine resolved the participant's symptoms. Six subjects from this study also reported development of herpes zoster. Because of timing, one case was ruled not to be related to vaccine administration. Of the five remaining cases, four were reported in the 3′-AmNic-rEPA vaccine recipients and one was reported in the placebo group.
Capitalizing on a higher antibody response with more frequent dosing, an independent, phase II trial was undertaken to further explore the optimal vaccine regimen. A total of 74 participants received injections of the 400-μg nicotine vaccine at 0, 4, 8, 12, 16, and 26 weeks. The additional injection allowed more than 80% of subjects to achieve nicotine-specific antibody levels above the target threshold of 25 μg/ml by week 14.
Two phase III clinical trials with the 3′-AmNicrEPA vaccine are ongoing. Each are double-blind, placebo-controlled, multicenter trials involving 1000 participants aged 18–65 years, smoking at least 10 cigarettes/day and interested in quitting smoking.[20,21] Exclusion criteria were systemic corticosteroid use, cancer or treatment for cancer within the last 5 years, human immunodeficiency virus infection, drug or alcohol abuse within the previous 12 months, and presence of cardiovascular, hepatic, renal, psychiatric, or respiratory disease. The primary end point for these studies is smoking abstinence at 12 months confirmed through patient report and carbon-monoxide levels. Secondary end points, such as withdrawal symptoms, cigarette consumption, and nicotine dependence, will be evaluated. Participants are receiving 400-μg injections of the 3′-AmNic-rEPA vaccine or placebo once/month for 6 months. Based on previous data, a target quit date set at week 14 will be used. Behavioral counseling will be included as an additional intervention in these trials. Patients will be followed for an additional 6 months after the last vaccination.
Pharmacotherapy. 2011;31(7):703-713. © 2011 Pharmacotherapy Publications
Cite this: Nicotine Conjugate Vaccine as a Novel Approach to Smoking Cessation - Medscape - Jul 01, 2011.